Behavioural NeurologyThe spectrum of language impairments in amyotrophic lateral sclerosis
Introduction
Amyotrophic lateral sclerosis (ALS) is the most common form of the progressive neurodegenerative disorder of motor neuron disease (MND), involving both upper and lower motor neuron signs. In addition, cognitive and/or behaviour changes are estimated to occur in up to 50% of ALS patients, with ~15% fulfilling criteria for frontotemporal dementia (FTD) and a further 30–40% showing mild to moderate cognitive impairments that mirror FTD clinical symptoms (Ringholz et al., 2005; Strong et al., 2017). These cognitive changes have generally involved executive dysfunction; however, there is evidence that language impairments are common and can occur without executive dysfunction or dementia (Rakowicz & Hodges, 1998; Taylor et al., 2012). Subsequently, this has led to the inclusion of language impairments in the recently revised diagnostic criteria (Strong et al., 2017).
Early investigations of language changes focused on characterising ALS patients with aphasia (Bak, O’Donovan, Xuereb, Boniface, & Hodges, 2001; Bak & Hodges, 2004). From this arose a prominent theory that proposed that a selective impairment in processing actions was a distinctive language feature of ALS (Bak, O'Donovan, Xuereb, Boniface & Hodges, 2001; Bak & Hodges, 2004; Grossman et al., 2008; Taylor et al., 2012; York et al., 2014). Specifically, ALS patients have shown a selective action naming and comprehension impairment, in the context of intact object naming and comprehension, compared to both age-matched controls and other pathologies (e.g., Alzheimer's disease; Bak & Hodges, 2001; Parkinson’s disease; York et al., 2014). Further, Grossman et al. (2008) found a relationship between motor cortex atrophy and knowledge of actions in ALS patients, which was not evident for object knowledge. Bak and Chandran (2012) thus proposed the notion that ‘what wires together dies together’ in that language deficits reflect impairments that are functionally connected to motor-system degeneration. However, there is ongoing speculation about whether there is an impairment of both action naming and the underlying semantic knowledge about actions, and whether an action impairment occurs in ALS patients without aphasia (Papeo et al., 2015).
Broadly speaking, language symptoms in ALS mirror the two main language FTD variants: progressive non-fluent aphasia (PNFA) that encompasses difficulties with the production and expression of language resulting in non-fluent output (Lillo & Hodges, 2009) and semantic dementia (SD) that encompasses difficulties with comprehension or receptive language skills (i.e. semantics; Gorno-Tempini et al., 2011; Bak & Hodges, 2001). The development of weakness of bulbar muscles leading to motor-speech deficits can hamper detection of language impairments, highlighting the challenges of testing language in ALS (Strong et al., 2017). Additionally, a recent systematic review of language in ALS-FTD indicated that population studies are needed to address the incidence of language impairments across the ALS-FTD spectrum, not just in cases of ALS with aphasia (Pinto-Grau, Hardiman, & Pender, 2018).
Naming ability is a commonly reported language impairment in ALS patients without FTD with an estimated 10–30% of ALS patients scoring below the 5% cut-off on naming tests (Abe et al., 1997; Abrahams et al., 2004; Hanagasi et al., 2002; Lomen-Hoerth et al., 2003; Mantovan et al., 2003; Massman et al., 1996; Raaphorst, de Visser, Linssen, de Haan, & Schmand, 2010; Wicks et al., 2009). There is evidence to suggest that aphasia may occur more frequently in rapidly progressing ALS cases (Bak et al., 2001; Caselli et al., 1993; da Rocha et al., 2007) although the exact prevalence is unknown (Pinto-Grau et al., 2018).
Syntactic comprehension deficits are commonly reported in ALS patients with dementia (Kamminga et al., 2016; Rakowicz & Hodges, 1998; Taylor et al., 2012; Yoshizawa et al., 2014); in addition, these deficits are independent of executive and visuospatial dysfunction (Yoshizawa et al., 2014). However, Kamminga et al. (2016) found it was only their ALS-FTD patients who performed significantly worse than controls on a sentence comprehension task whereas their cognitively intact ALS group performed comparable to controls.
Verbal fluency impairments in ALS have been one of the most consistently noted deficits in ALS patients without cognitive impairment (Abrahams et al., 1995, 1996, 2000, 2005; Kew et al., 1993; Quinn et al., 2012). Although performance on verbal fluency tasks can be confounded by motor and language deficits in ALS, possibly exaggerating the estimates of true cognitive deficits (Abrahams et al., 2000; Strong et al., 1999), pronounced verbal fluency deficits observed in bulbar patients remain even after controlling for the presence of dysarthria (Abrahams et al., 1997; Schreiber et al., 2005; Strong et al., 1999). Abrahams et al. (2000) investigated the use of written verbal fluency controlling for hand motor speed to try to eliminate the impact of motor speech deficits on spoken verbal fluency performance. They found patients were impaired compared to controls on written verbal fluency measures, which they reasoned indicated dysfunction in intrinsic response generation in ALS, rather than a deficit in producing spoken language per se. As such, verbal fluency deficits elicited by a letter, is now included in the ALS diagnostic criteria (Strong et al., 2017).
Speech production in ALS is often impacted by dysarthria and dysphagia, which can lead to reduced verbal output, complete mutism or cessation of communication regardless of motor difficulties (Bak & Hodges, 1999, 2001, 2004; Lillo & Hodges, 2009). Of note, in some cases reduced speech and mutism are reported to occur prior to the onset of signs of dysarthria (Bak & Hodges, 2001, 2004). On spontaneous speech tasks that involve the production of multiple connected sentences, ALS patients produce a lower propositional speech rate (i.e., fewer words) compared to matched healthy controls (Ash et al., 2015; Tsermenseli et al., 2016). However, speech production rate differences disappeared when Ash et al. (2015) removed patients with dysarthria and executive function impairment from the analysis, which suggests that the impact of bulbar symptoms and other cognitive skills on speech rate is yet to be explored.
Reduced spontaneous (or propositional) speech in the context of well-preserved naming, repetition, comprehension and reading skills is the hallmark of the language disorder of dynamic aphasia (Luria, 1972; Robinson, Blair, & Cipolotti, 1998; Rohrer et al., 2008), with some severe cases also showing poor verbal fluency. Dynamic aphasia and the two FTD language variants have been associated with focal neurodegeneration. For example, dynamic aphasia has been attributed to a language-specific selection deficit that is associated with left inferior frontal gyrus (LIFG) atrophy or damage (Robinson et al., 1998; Robinson Shallice & Cipolotti, 2005); PNFA has been associated with atrophy in the LIFG and insular regions (Nestor et al., 2003); and SD has been associated with atrophy in the anterior and inferior temporal lobes (Hodges & Patterson, 2007).
Although dynamic aphasia has not, to our knowledge, been reported or investigated in ALS, given the possible subtle language changes in ALS including evidence for reduced spontaneous speech rate, it is a focus yet to be investigated. Interestingly, the dynamic aphasia case CH (Robinson, Shallice, & Cipolotti, 2005) showed LIFG dysfunction similar to the ALS–aphasia cases reported by Bak et al. (2001).
Thus, it appears that there is a spectrum of language disorders and severity. One reason for the disparity was raised by Raaphorst et al. (2010) who reasoned that the underlying disease process in ALS may affect differing cortical networks in different individuals, which would explain some of the lack of agreement regarding language. A recent meta-analysis noted that of the 55 language studies in ALS, only eight use five or more language tests (Pinto-Grau et al., 2018). In addition, Rakowicz and Hodges (1998) highlight the usefulness of adopting both group and case analysis in understanding the varied language impairments in ALS. Therefore, in the current study we assess an unselected group of ALS patients (i.e., patients were not selected based on their level of cognitive or language impairments) with a comprehensive language battery designed to assess a wide range of language skills in order to characterise the language signature across the ALS spectrum.
In order to characterise the language profile of an unselected ALS group, performance was assessed on 11 tasks that measured spontaneous speech, repetition, naming, auditory comprehension, sentence completion/generation and semantic memory. At a group level, it was predicted that ALS patients would show poorer performance on tests of language in comparison to matched healthy controls. Furthermore, we aimed to determine if we could find a pronounced action processing deficit (Bak & Hodges, 2004, 2001; Grossman et al., 2008), as assessed by naming and semantic memory tests, in an unselected sample. While there is evidence for dissociation of actions and objects in ALS, it is unclear if this pattern occurs in all ALS cases with extra-motor involvement or if this pattern is only found in cases of ALS-aphasia.
We aimed to identify specific language phenotypes in ALS through a case series analysis. A continuum of language symptoms was expected in this unselected sample, with some cases fulfilling criteria for ALS-FTD. In addition, we hypothesised that some cases would resemble the signature of frontal dynamic aphasia, albeit mild; hence complex scene description and sentence completion/generation tests were given to investigate spontaneous speech and the selection process.
Section snippets
Methods
We report how we determined our sample size, all data exclusions (if any), all inclusion/exclusion criteria, whether inclusion/exclusion criteria were established prior to data analysis, all manipulations, and all measures in the study.
Demographics and cognitive baselines
As seen in Table 3, groups were well matched for age, education, sex and handedness and there was no significance difference between groups for premorbid IQ, current IQ, verbal inhibition (Hayling), attention (Digit Span), self-rated apathy or depression. Apart from three control participants with reduced Hayling Test performances, control participants were above the 5th percentile on all cognitive measures. ALS patients reported a significantly higher number of symptoms of anxiety than
Discussion
The current study systematically characterised the language impairments alongside other cognitive and behavioural symptoms in an unselected ALS sample as a group and, given the heterogeneity of ALS, as a case series. We show a pattern of cognitive, language and behavioural deficits supporting the increasingly accepted notion of ALS as a multi-system disorder (Ringholz et al., 2005; Strong et al., 2017; Tsermentseli, Leigh, & Goldstein, 2012).
Conclusion
Overall, we have characterised the language impairments alongside other cognitive and behavioural symptoms of an unselected ALS sample as a group and, given the heterogeneity of ALS, as a case series. In line with recent suggestions, our ALS patients’ action naming deficit does not support the notion that action processing may be selectively impaired in ALS. Rates of cognitive and behavioural impairment were consistent with the literature. The most prominent language feature in the ALS group
CRediT author statement
Amelia Ceslis – Conceptualization, Methodology, Formal analysis, Data Curation, Project administration, Writing - Original Draft, Review & Editing.
Rosemary Argall – Methodology, Investigation, Data Curation, Writing – Original Draft Project administration.
Robert Henderson – Resources, Data Curation, Writing - Review & Editing.
Pamela McCombe – Resources, Writing - Review & Editing.
Gail A Robinson – Conceptualization, Methodology, Investigation, Resources, Data Curation, Writing - Original Draft,
Acknowledgements
We wish to thank the participants and their families for generously giving their time for this study. We also thank Kate Thorpe and Susan Heggie for assisting with recruitment and Amelia Hobson for assisting with data collection. G.R. is currently supported by an Australian National Health and Medical Research Council (NHMRC) Boosting Dementia Research Leadership Fellowship (APP1135769).
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